How do free fatty acids affect the severity of a heart attack?

In the previous two posts, I wrote about hypoxia and pseudohypoxia, i.e. the state of lack of oxygen or just the signaling of lack of oxygen in the tissues. I predicted that free long-chain fatty acids (abbreviation FFA or NEFA), by strongly modulating the activity of the enzyme glutathione peroxidase (GPx), would likely strongly influence oxygen deficiency signaling through the transcription factor HIF-1α whose proper and adequate stabilization requires some, not too little or too much hydrogen peroxide H2O2. Too high a peroxide level will be typical in pseudohypoxia, and too low will cause an insufficient and therefore potentially very dangerously low response to oxygen deficiency. The two conditions can be quite intertwined and can occur simultaneously in different tissues and also the conditions will depend heavily on the specific ones in the tissue. It seems that if, for example, the heart muscle suffers from insulin  resistance and therefore also a mild pseudohypoxia, it can still use oxidative phosphorylation during hypoxia and does not switch to fermentation, which would not need precious oxygen. Precisely this case is confirmed in the study of the heart after a heart attack, in the state of insulin resistance and high level of free fatty acids in the blood, which is typical in diabetes. And they attributes this effect to the lack of succinate.

Let's see what the authors of this study found, let's show some graphs.

Free fatty acids (NEFA) are elevated in diabetes, the higher they are, the worse the cells will react to lack of oxygen (HIF-1α).

Artificially induced insulin resistance of heart cells manifests itself as a poor adaptation to lack of oxygen, the fermentation of glucose to lactate is reduced and its use is reduced. This will worsen the prognosis of successfully overcoming a heart attack. (white = normoxia, black = hyxpoxia)

This is due to insufficient stabilization of the HIF-1α factor and will be manifested by insufficient glucose intake in the absence of oxygen.

Stabilization of HIF-1α and fermentation of glucose to lactose is inversely proportional to the level of FFA (Palmitate, Oleate) and the sensitivity is different for different fatty acids. By adding SSO to prevent FFA to enter the cell, the effect of insulin resistance can be compensated (HIR + SSO).

The negative effect of long fatty acids on behavior in hypoxia can be compensated by increasing the level of succinate or substances from which the cell restores it, here they supplemented with dimethyl fumarate DMF (ie, MCT oil should have a very similar effect, as it supports omega oxidation and the formation of succinate and takes down long-chain FFA).

Similarly, agents that limit HIF-1α tagging for removal (DMOG) are able to offset the effects of insulin resistance.

It can be seen that influencing the metabolism using different fats can be compensated by other substances or other fats. Evolution seems to have ensured a balanced metabolism with a diet containing different fats, and also ensured the possibility of programming the metabolism with fats for different situations. We are still fumbling and the meaning of these adaptations escapes us. We program our metabolism for different conditions than those to which our body is exposed. Then we can't be surprised that the cells are confused and behave differently than we would like. It requires an even better understanding of the meaning and principles of these adaptation mechanisms.

Supplement:

I still wonder what the mechanism of these phenomena is. After discovering that H2O2 is necessary for glucose to enter the cell at low insulin levels (fasting), I think the answer is already clear. Succinate cannot accumulate in the presence of free fatty acids due to the high activity of glutathione peroxidase. The lack of H2O2 will limit the entry of glucose into the cell, thus causing insulin resistance. The missing glucose is also the substrate for the production of succinate, so it will also be in short supply and HIF-1 activation will be suppressed. But this is not the standard situation when burning fats, because peroxisomes also participate in it and they themselves produce enough H2O2. In addition, fasting or medium-chain fats activate omega oxidation of fats, and peroxisomes form succinate from the dicarboxylic acids thus formed. In a real situation, the activation of HIF-1 during hypoxia will occur normally without restrictions even during fat burning.

Next

Previous

References:

Fatty Acids Prevent Hypoxia-Inducible Factor-1a Signaling Through Decreased Succinate in Diabetes